He played running back for Rutherford High School in Panama City, Florida, but switched to linebacker before his senior year.

He was chosen as the USA Today Florida Player of the Year for his efforts as a senior, where he posted 112 tackles, 3 sacks, and three interceptions.

Despite the loss of key personnel like defensive tackle Kris Jenkins, the Panthers led the league in interceptions.

In 2005, his final year with the Panthers, Witherspoon played in 15 games and finished the season 81 tackles, 2.5 sacks and two interceptions.

[4][5] On October 20, 2009, Witherspoon was traded from the Rams to the Philadelphia Eagles in exchange for wide receiver Brandon Gibson and a fifth round draft pick in 2010.

In his first game as an Eagle against the Washington Redskins on October 26, 2009, he recorded six tackles, an interception (returned for a touchdown), sack, and a forced fumble.

He was voted by his teammates as the Titans Ed Block Courage Award recipient [7] On July 18, 2013, Witherspoon signed with the Rams.